Intrabuccally rapidly disintegrating tablet and a production method of the tablets

ABSTRACT

An intrabuccally rapidly disintegrating tablet which is manufactured by a simple method, has an enough practical hardness and is rapidly disintegrated in the buccal cavity and its production method. The intrabuccally rapidly disintegrating tablet is produced by growing a powder material into a granulated material with a fixed particle diameter, the powder material including a sugar alcohol or a saccharide as main ingredient, each of which is first particle having an average particle diameter of not more than 30 μm, by mixing thus obtained granulated material with an active ingredient and a disintegrant, and by compressing the mixture into a predetermined shape.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional and claims the benefit under 35 U.S.C.§120 of U.S. patent application Ser. No. 10/356,641, filed on Jun. 20,2003, which is a continuation-in-part of U.S. application Ser. No.09/147,374, filed on Jun. 4, 1999, now abandoned, which is a NationalStage entry of PCT/JP97/02032, filed on Jun. 12, 1997. The entirecontent of these prior applications is fully incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to tablets rapidly disintegrable in the buccalcavity.

2. Prior Art

There are various types of oral administrative medicines: tablets,capsules, granules, powders, syrups and so on. However, such oraladministrative medicines have several problems as follows. As to tabletsand capsules, for example, it may be hard for aged person or childrenwhose swallowing power is weak to swallow them. And as to granules andpowders, they may cause unpleasantness in the mouth after dosage or theymay erroneously happen to enter into a respiratory tract or lungs.Further, they can't be taken where there is no water because water isusually required for dosage. As for syrups, it may be difficult for agedpersons or children who can not measure them accurately to take them dueto the trouble of measuring them for dosage.

On the other hand, solid medicines which can be rapidly dissolved ordisintegrated in the buccal cavity can be taken without measuring norwater, so they may be easily taken by such aged persons or children.Further, such solid medicines can be taken without water.

By the way, there have been developed several types of medicines whichcan be rapidly dissolved or disintegrated in the buccal cavity ondosing.

For instance, in JP-B-62-50445, solid medicines which can be producedfrom water solution that mainly contains gelatin including an activeingredient by use of freeze drying method are disclosed. And inWO93/12769, solid medicines which can be produced by drying suspensionincluding agar are also disclosed. However, the medicines produced bythe above-mentioned prior methods do not have enough hardness to betaken by pushing out of PTP packages (Press Through Pack) containing themedicines. And, they require a special pharmaceutical technique and alsorequire an enormous investment in plants and equipments.

JP-A-5-271054 and WO93/15724 disclose production methods of tabletswherein tablets composed of a saccharide are produced in such a mannerthat a saccharide mixture supplied with appropriate water is compressedat a low pressure and then dried to make solid tablets. However, suchmethods also require a special pharmaceutical technique and have thefear that powder composing the tablets may be adhered to the surface ofa metal mold in compression process under moistening condition. It maybe therefore difficult to utilize those methods in manufacturing use ina plant.

SUMMARY OF THE INVENTION

From the several pharmaceutical points of view, the inventors of thepresent invention have examined intrabuccally rapidly disintegratingtablets which don't require a special pharmaceutical productiontechnique and can be simply and easily produced by a normal equipment.As a result, they have developed, as new pharmaceutical tablets,compressed tablets produced by mixing a sugar alcohol such as D-mannitoland a lactose or a saccharide which have an average particle diameter ofnot more than 30 μm (first particle), an active ingredient and adisintegrant, by granulating the mixture to obtain a granulated material(second particle), and by compressing the granulated material. Thetablets can be disintegrated in a buccal cavity within one minute andhave hardness without a trouble for practical use, although it has beenconsidered unable to produce for long time.

The present invention relates to the followings;

(1) An intrabuccally rapidly disintegrating tablet comprising: a sugaralcohol or a saccharide, each of which is first particle having anaverage particle diameter of not more than 30 μm; an active ingredient;and a disintegrant.

(2) An intrabuccally rapidly disintegrating tablet produced by: growinga powder material into a granulated material with a fixed particlediameter, the powder material comprising a sugar alcohol or asaccharide, each of which is first particle having an average particlediameter of not more than 30 μm; mixing thus obtained granulatedmaterial with an active ingredient and a disintegrant; and compressingthe mixture into a predetermined shape.

(3) An intrabuccally rapidly disintegrating tablet produced by: growinga mixture of a powder material and an active ingredient into agranulated material with a fixed particle diameter, the powder materialcomprising a sugar alcohol or a saccharide, each of which is firstparticle having an average particle diameter of not more than 30 μm;mixing thus obtained granulated material with a disintegrant; andcompressing the mixture into a predetermined shape.

(4) An intrabuccally rapidly disintegrating tablet produced by: growinga mixture of a powder material and a disintegrant into a granulatedmaterial with a fixed particle diameter, the powder material comprisinga sugar alcohol or a saccharide, each of which is first particle havingan average particle diameter of not more than 30 μm; mixing thusobtained granulated material with an active ingredient; and compressingthe mixture into a predetermined shape.

(5) An intrabuccally rapidly disintegrating tablet produced by: growinga mixture of a powder material, an active ingredient and a disintegrantinto a granulated material with a fixed particle diameter, the powdermaterial comprising a sugar alcohol or a saccharide, each of which isfirst particle having an average particle diameter of not more than 30μm; and compressing the mixture into a predetermined shape.

(6) The intrabuccally rapidly disintegrating tablet as set forth in theabove-mentioned (1)-(5) wherein the tablet is compressed into apredetermined shape after adding a lubricant in the granulated material.

(7) The intrabuccally rapidly disintegrating tablet as set forth in theabove-mentioned (1)-(5) wherein the tablet is compressed into apredetermined shape after applying a lubricant on material contactingsurfaces of punches and dies of a tabletting machine in advance prior tocompression procedure.

(8) The intrabuccally rapidly disintegrating tablet as set forth in theabove-mentioned (1)-(5) wherein the tablet contains an active ingredientin the amount of 0.01-30% by weight of the tablet, a disintegrant in theamount of 1-10% by weight of the tablet, a sugar alcohol or a saccharidein the amount of 60-95% by weight of the tablet.

(9) The intrabuccally rapidly disintegrating tablet as set forth in theabove-mentioned (1)-(5) wherein the tablet contains a disintegrant inthe amount of 1-10% by weight.

(10) The intrabuccally rapidly disintegrating tablet as set forth in theabove-mentioned (1)-(5) wherein the sugar alcohol is D-mannitol.

(11) The intrabuccally rapidly disintegrating tablet as set forth in theabove-mentioned (1)-(5) wherein the saccharide is a lactose.

(12) The intrabuccally rapidly disintegrating tablet as set forth in theabove-mentioned (1)-(5) wherein the disintegrant is at least oneselected from the group consisting of crosspovidone, crosscarmellosesodium, or low substituted hydroxypropycellulose.

(13) The intrabuccally rapidly disintegrating tablet as set forth in theabove-mentioned (1)-(5) wherein a disintegration time in the buccalcavity of the tablet is not more than 1 minute.

(14) The intrabuccally rapidly disintegrating tablet as set forth in theabove-mentioned (1)-(5) wherein the tablet has a hardness of 4 kg andthe tablet goes down through a No. 10 mesh wire within 30 seconds whenthe tablet is placed on the mesh wire and a drop of water is fallen ontothe tablet at a speed of 4 ml per minute.

(15) The intrabuccally rapidly disintegrating tablet as set forth in theabove-mentioned (1)-(5) wherein the sugar alcohol or the saccharide isprepared in advance to be pulverized into an average particle size ofnot more than 30 μm.

(16) A production method of an intrabuccally rapidly disintegratingtablet, comprising the steps of:

-   -   a) growing a powder material comprising a sugar alcohol or a        saccharide, each of which is first particle having an average        particle size of not more than 30 μm, into a granulated material        with predetermined size;    -   b) mixing thus obtained granulated material with an active        ingredient and a disintegrant, adding a lubricant; and    -   c) compressing the mixture thus produced as above into a        predetermined shape.

(17) A production method of an intrabuccally rapidly disintegratingtablet, comprising the steps of:

-   -   a) growing a mixture of a powder material and an active        ingredient, the powder material comprising a sugar alcohol or a        saccharide, each of which is first particle having an average        particle size of not more than 30 μm, into a granulated material        with a predetermined size;    -   b) mixing thus obtained granulated material with and a        disintegrant, adding a lubricant; and    -   c) compressing the mixture thus produced as above into a        predetermined shape.

(18) A production method of an intrabuccally rapidly disintegratingtablet, comprising the steps of:

-   -   a) growing a mixture of a powder material and a disintegrant,        the powder material comprising a sugar alcohol or a saccharide,        each of which is first particle having an average particle size        of not more than 30 μm, into a granulated material with a        predetermined size;    -   b) mixing thus obtained granulated material with an active        ingredient, adding a lubricant; and    -   c) compressing the mixture thus produced as above into a        predetermined shape.

(19) A production method of an intrabuccally rapidly disintegratingtablet, comprising the steps of:

-   -   a) growing a mixture of a powder material, an active ingredient,        and a disintegrant, the powder material comprising a sugar        alcohol or a saccharide, each of which is first particle having        an average particle size of not more than 30 μm, into a        granulated material with a predetermined size;    -   b) mixing thus obtained granulated material, adding a lubricant;        and    -   c) compressing the mixture thus produced as above into a        predetermined shape.

(20) The production method of an intrabuccally rapidly disintegratingtablet as set forth in the above-mentioned (16)-(19) wherein the sugaralcohol or the saccharide is prepared in advance to be pulverized intoan average particle size of not more than 30 μm.

(21) A production method of an intrabuccally rapidly disintegratingtablet, comprising the steps of:

-   -   a) growing a powder material comprising a sugar alcohol or a        saccharide, each of which is first particle having an average        particle size of not more than 30 μm, into a granulated material        with a predetermined size;    -   b) mixing thus obtained granulated material with an active        ingredient and a disintegrant, without adding a lubricant; and    -   c) further comprising the steps for compressing the mixture thus        produced as above;    -   d) spraying a lubricant on material contacting surfaces of        punches and dies of a tabletting machine as a pre-compression        step; and    -   e) compressing the mixture supplied to the die of the tabletting        machine into a predetermined shape.

(23) A production method of an intrabuccally rapidly disintegratingtablet, comprising the steps of:

-   -   a) growing a mixture of a powder material and an active        ingredient, the powder material comprising a sugar alcohol or a        saccharide, each of which is first particle having an average        particle size of not more than 30 μm, into a granulated material        with a predetermined size;    -   b) mixing thus obtained granulated material with a disintegrant,        without adding a lubricant; and    -   further comprising the steps for compressing the mixture thus        produced as above;    -   c) spraying a lubricant on material contacting surfaces of a        punches and dies of a tabletting machine as a pre-compression        step; and    -   d) compressing the mixture supplied to the die of the tabletting        machine into a predetermined shape.

(23) A production method of an intrabuccally rapidly disintegratingtablet, comprising the steps of:

-   -   a) growing a mixture of a powder material and a disintegrant,        the powder material comprising a sugar alcohol or a saccharide,        each of which is first particle having an average particle size        of not more than 30 μm, into a granulated material with a        predetermined size;    -   b) mixing thus obtained granulated material with an active        ingredient, without adding a lubricant; and    -   further comprising the steps for compressing the mixture thus        produced as above;    -   c) spraying a lubricant on material contacting surfaces of        punches and dies of a tabletting machine as a pre-compression        step; and    -   d) compressing the mixture supplied to the die of the tabletting        machine into a predetermined shape.

(24) A production method of an intrabuccally rapidly disintegratingtablet, comprising the steps of:

-   -   a) growing a mixture of a powder material, an active ingredient        and a disintegrant, the powder material comprising a sugar        alcohol or a saccharide, each of which is first particle having        an average particle size of not more than 30 μm, into a        granulated material with a predetermined size;    -   b) mixing thus obtained granulated material without adding a        lubricant; and further comprising the steps for compressing the        mixture thus produced as above into a predetermined shape;    -   c) spraying a lubricant on material contacting surfaces of        punches and dies of a tabletting machine as a pre-compression        step; and d) compressing the mixture supplied to the die of the        tabletting machine into a predetermined shape.

(25) The production method of an intrabuccally rapidly disintegratingtablet as set forth in the above-mentioned (21)-(24) wherein the sugaralcohol or the saccharide is prepared in advance to be pulverized intoan average particle size of not more than 30 μm.

(26) An intrabuccally rapidly disintegrating tablet comprising: a sugaralcohol or a saccharide of which average particle size is not more than30 μm as a main ingredient; an active ingredient; and a disintegrant,wherein the main ingredient is contained in the amount of 60-95% byweight of the tablet and the disintegrant is contained in the amount of1-10% by weight of the tablet.

(27) The intrabuccally rapidly disintegrating tablet as set forth in theabove-mentioned (26), the tablet is produced by: granulating a mixtureof the main ingredient, the active ingredient and the disintegrant;mixing thus granulated material with a fixed amount of lubricant and arequired adjuvant; and compressing thus mixed material into apredetermined shape.

(28) The intrabuccally rapidly disintegrating tablet as set forth in theabove-mentioned (26), the tablet is produced by: granulating a mixtureof the main ingredient, the active ingredient and the disintegrant;mixing thus granulated material without adding a lubricant; applying alubricant on punches and dies of a tabletting machine; and compressingthus mixed material into a predetermined shape.

(29) The intrabuccally rapidly disintegrating tablet as set forth in theabove-mentioned (26)-(28) wherein the main ingredient is either one ofD-mannitol or a lactose.

(30) The intrabuccally rapidly disintegrating tablet as set forth in theabove-mentioned (26)-(29) wherein the disintegrant is at least oneselected from the group consisting of crosspovidone, crosscarmellosesodium, or low substituted hydroxypropycellulose.

(31) The intrabuccally rapidly disintegrating tablet as set forth in theabove-mentioned (30) wherein the tablet contains 1 to 30 mg disintegrantfor one dosage.

(32) A production method of an intrabuccally rapidly disintegratingtablet comprising a sugar alcohol or a saccharide of which averageparticle size is not more than 30 μm as a main ingredient, an activeingredient, and a disintegrant wherein the main ingredient is contained60-95% by weight of the tablet and the disintegrant is contained 1-10%by weight of the tablet, comprising the steps of: producing a mixture ofthe main ingredient, the active ingredient and the disintegrant; mixingthe mixture with a fixed amount lubricant and a required adjuvant; andcompressing thus mixed material into a predetermined shape.

(33) A production method of an intrabuccally rapidly disintegratingtablet comprising a sugar alcohol or a saccharide of which averageparticle size is not more than 30 μm as a main ingredient, an activeingredient, and a disintegrant wherein the main ingredient is containedin the amount of 60-95% by weight of the tablet and the disintegrant iscontained in the amount of 1-10% by weight of the tablet, comprising thesteps of: producing a mixture of the main ingredient, the activeingredient and the disintegrant; granulating the mixture into apredetermined size; mixing thus granulated material with a requiredadjuvant without adding a lubricant; applying a lubricant on punches anddies of a tabletting machine; and compressing thus mixed material into apredetermined shape.

Generally, first particle refers to single particle of raw material. Inthis specification, first particle means a single particle of rawmaterial in nature and doesn't mean particle of an aggregation.Generally, second particle refers to particle in which special processis executed for the first particle. Second particle in thisspecification means particle after some process such as granulation isexecuted, namely particle of granulated material which is an aggregationof first particle (for example granule).

The object of the present invention is to provide an intrabuccallyrapidly disintegrating tablet which includes a sugar alcohol or asaccharide of which is first particle having not more than 30 μm inaverage particle size, further includes an active ingredient and adisintegrant and which is produced by compressing into a predeterminedshape.

The method of producing the intrabuccally rapidly disintegrating tabletaccording to the present invention includes an internal lubricationmethod in which a powder material and a lubricant are mixed beforecompression and an external lubrication method in which a lubricant isapplied on punches and dies of a tabletting machine before compression.

D-mannitol can be used as a sugar alcohol in the present invention, anda lactose can be used as a saccharide. At least one kind of a sugaralcohol or a saccharide is used.

As active ingredients, followings are used, but other ingredients fororal administration can be also used.

<Drug for Central Nervous System>

hyprotics, anxiolytics . . . amobarbital, alprazolam, flurazepamhydrochloride, diazepam, and so on

NTHEs/antiepileptic . . . valproate sodium, nitrazepam, phenytoin, andso on

analgesic antipyretic agent . . . aspirin, acetaminophen, ibuprofen,diclofenac sodium, ethenzamide, indometacin and so on

drug for Pakinson's disease . . . levodopa, amantadine hydrochloride,trihexyphenidyl hydrochloride, piroheptine hydrochloride, and so on

psychoneurosis agent . . . etizolam, amitriptyline hydrochloride,sulpiride, and so on

<Drug for Peripheral Nervous System>

skeletal muscle relaxant . . . chlorphenesin carbamate, chlormezanone,and so on

autonomic nervous agent . . . valethamate bromide, tofisopam, and so on

antispasmodic . . . afloqualone, and so on

<Drug for Circulatory>

cardiac . . . ubidecarenon, aminophylline, etilefrine hydrochloride, andso on

antiarrhythmic agents . . . atenolol, pindolol, and so on

diuretic . . . spironolactone, trichlormethiazide, furosemide, and so on

antihypertensive agent . . . todrazine hydrochloride, nicardipinehydrochloride, hydralazine hydrochloride, and so on

angiotonic . . . dihydroergotamine mesilate and so on

vasodilator . . . benidipine hydrochloride, diltiazem hydrochloride,isosorbide dinitrate, and so on

hyperlipemia . . . clinofibrate, nicomol, and so on

others . . . flunarizine hydrochloride, meclofenoxate hydrochloride,cinnarizine, and so on

<Antidiarrhea>

antidiarrhoeic . . . loperamide hydrochloride, dimeticone, and so on

drug for peptic ulcer . . . azulene, L-glutamine, aceglutamidealuminium, cetraxate hydrochloride, cimetidine, and so on

cholagogue . . . anetholtrithion, chenodeoxycholic acid, and so on

others . . . donperidone, trimebutine maleate, metoclopramide,cisapride, and so on

<Metabolic Drug>

vitamin . . . alfacarcidol, tiamine hydrochloride, cobamide, vitaroxin,riboflavin butyrate, ascorbic acid, phytonadione, and so on

diabetes mellitus agent . . . glybuzole, tolbutamide, and so on

<Antiallergies>

antihistamine . . . homochlorcyclizine hydrochloride, clemastinefumarate, chlorpheniramine maleate, and so on

others . . . oxatomide, ketotifen fumarate, azelastin hydrochloride, andso on

<Antineoplastics>

metabolic antagoism agent . . . fluorouracil, tegafur, and so on

<Antibiotics>

paromomycin sulfate, amoxicillin, cefaclor, cefalexin, acetylspiramycin,minocycline hydrochloride

Wherein such as crosspovidone, cross sodium carboxymethyl cellulose, lowsubstituted hydroxypropylcellulose or the like, which are widely usedfor drugs and food can be used as a disintegrant. At least one kind ofdisintegrant is used.

Next, a production method of tablets according to the present inventionwill be described hereinafter.

The tablets of the present invention can be obtained by compressing andtabletting after granulating a mixed powdered components containing asugar alcohol or a saccharide of which is first particle having anaverage particle diameter of not more than 30 μm, an active ingredient,and a disintegrant by means of a hammer mill, a jet mill or the like.

The amount of sugar alcohol or saccharide is preferably about 60-95weight % in the amount of a resulting tablet, more preferably about80-95 weight % of a resulting tablet.

The amount of active ingredient is different depending on the kind anddosage amount of active ingredient, however, about 0.01-30 weight % inthe amount of a resulting tablet is preferable, and more preferablyabout 0.01-10 weight % of a resulting tablet.

The amount of disintegrant present is preferably about 1-30 mg perdosage, and more preferably about 1-10 weight % in the amount of aresulting tablet.

A granulation method isn't limited, however a wet granulation methodusing purified water, ethanol or the like can be preferably used. In themethod, for example, granulation can be executed by means of a fluid-bedgranulator, a rotary stirring granulator or an extruding granulator. Thegranulated material is dried, mixed with a lubricant, and thereaftercompressed into a predetermined shape. Binders, sour agents, foamingagents, sweetening agents, flavoring agents, or colorants can be addedas additives. Otherwise, a dry granulation method may be used.

As a lubricant, such as magnesium stearate, calcium stearate stearicaid, stearic acid, stearyl alcohol, sucrose esters of fatty acid, talc,light anhydrous silicic acid, or like present. Binders present, forexample, hydroxypropyl-cellulose, polyvinylphrrolidone,hydroxypropyl-methylcellulose, partially saponificated polyvinylalcohol, methylcellulose, pullulan or the like. Sour agents presentcitric acid, malic acid, adipic acid, ascorbic acid, and the like.Foaming agents are sodium bicarbonate, sodium carbonate, calciumcarbonate, and the like. Sweetening agents are aspartame (TM),saccharin, glycyrrhizic acid or the like. Flavoring agents are lemon,orange, pine, mint, menthol or the like. Colorants are yellow ironsesquioxide, red iron sesquioxide, tar color or the like.

The amount of lubricant is preferably about 0.01-2 weight % in theamount of a tablet and more preferably about 0.01-0.5 weight %.

Such an intrabuccally rapidly disintegrating tablet of the presentinvention can be produced by an internal lubrication method wherein alubricant is internally contained in the tablet by mixing a lubricantinto the granule prior to compression. Further, it can be produced alsoby an external lubrication method wherein a lubricant isn't included inthe tablet and is externally attached to the outer surface of the tabletby applying a lubricant onto the material contacting surfaces of punchesand dies of a tabletting machine.

In both of the internal lubrication method and the external lubricationmethod, there are several compression methods: after granulating a sugaralcohol or a saccharide, an active ingredient and a disintegrant aremixed and compression is executed; after granulating a sugar alcohol ora saccharide and an active ingredient, a disintegrant is mixed andcompression is executed; after granulating a sugar alcohol or asaccharide and a disintegrant, an active ingredient is mixed andcompression is executed; after granulating a sugar alcohol or asaccharide, an active ingredient and a disintegrant, compression isexecuted.

Although a tabletting method isn't limited in the present invention, arotary tabletting machine, a hydraulic press machine or a single punchtabletting machine which have high productivity can be more preferablyused.

The shape of tablets obtained in the present invention can be pills orother shapes such as normal R surface (concave plane surface) tablets, asugar coated R surface tablets, tablets with square edges, tablets withrounded edges, or tablets with two R surfaces, or the like.

The tablet may be a dividable tablet with a dividing line.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention will be concretely explained according topreferable embodiments and comparative embodiments as described infollowing experimental data.

[Comparison 1]

1890 g of D-mannitol (Towa Kasei Co., Ltd., average particle diameter ofabout 60 μm) and 100 g of crosspovidone (POLYPLASDONE XL-10: GAF Co.,Ltd.) were fed in a fluid-bed granulation dryer (Gratt Co., Ltd.:WSG-type 5), and purified water was sprayed in the dryer to produce agranulated material and the material thus grown after the granulationwas dried. 10 g of magnesium stearate was added and mixed with thegranulated material, and they were compressed and tabletted with arotary tabletting machine (Kikusui Co., Ltd., clean press collect type12) in which the tabletting conditions were as follows; tablet weightwas 200 mg, a metal mold was 8 mm diameter flat-type, and compressionpressure was varied such as 150 kg, 300 kg, 450 kg, 600 kg, and 800 kgto produce resulting tablets.

Embodiment 1

D-mannitol (Towa Kasei Co., Ltd.: average particle diameter of about 60μm) was previously ground by a jet mill (Japan Pneumatic Co., Ltd.: typePJM-I-1.5) and the pulverized D-mannitol with average particle diameterof 20 μm was obtained. 1890 g of the pulverized D-mannitol and 100 g ofcrosspovidone (POLYPLASDONE XL-10: GAF Co. Ltd.) were fed in a fluid-bedgranulation dryer (Gratt Co., Ltd.: WSG-type 5), purified water wassprayed, and a granulated material was obtained after granulation anddrying process. 10 g of magnesium stearate was added and mixed with thegranulated material and they were compressed and tabeletted with arotary tabletting machine (Kikusui Co., Ltd., clean press collect type12) in which tabletting conditions were the same as that in theComparison 1.

[Comparison 2]

100 g of donperidone, gastrointestinal motility improvement agent, 1790g of lactose (DMV Co., Ltd.: average particle diameter of about 80 μm)and 100 g of crosspovidone (POLYPLASDONE XL-10: GAFCo., Ltd.) were fedin a fluid-bed granulation dryer (Gratt Co., Ltd.: WSG-type5), purifiedwater was sprayed in the dryer, and a granulated material was obtainedafter granulation and drying process. 10 g of magnesium stearate wasadded and mixed with the granulated material and they were compressedand tabeletted with a rotary tabletting machine (Kikusui Co., Ltd.:CLEAN PRESS COLLECT type 12) in which tabletting conditions were thesame as that in the Comparison 1.

Embodiment 2

Lactose (DMV Co., Ltd.: average particle diameter of about 80 μm) waspreviously ground by a jet mill (Japan Pneumatic Co., Ltd.: typePJM-I-1.5) to produce pulverized lactose with average particle diameterof 15 μm. 1790 g of the pulverized lactose, 100 g of donperidone, and100 g of crosspovidone (POLYPLASDONE XL-10: GAF Co., Ltd.) were fed in afluid-bed granulation dryer (Gratt Co., Ltd.: WSG-type 5), purifiedwater was sprayed in the dryer, and a granulated material was obtainedafter granulation and drying process. 10 g of magnesium stearate wasadded and mixed with the granulated material and they were compressedand tabeletted with a rotary tabletting machine (Kikusui Co., Ltd.,CLEAN PRESS COLLECT TYPE 12) in which tabletting conditions were thesame as that in the Comparison 1.

Embodiment 3

The granulated material obtained in the Embodiment I was tabletted underthe condition that the tablet weight was 200 mg and the compressionpressure was 50 kg/cm², and a little magnesium stearate was coated on ametal mold (8 mm diameter flat-type) and dies of a hydraulic pressmachine (Riken Seiki Co., Ltd.: type P-1B) to obtain a tablet.

Table 1 shows the evaluation result of the hardness and disintegrationtime of the tablets obtained by the Embodiments 1 and 2 and theComparisons 1 and 2.

The hardness of the tablets was measured by a tablet destructivestrength measuring instrument (Toyama Sangyo Co., Ltd.: TH-203CP type),and as for the disintegration time test of the tablets, a uniquemeasuring method (called as DW (Drops Water) method hereinafter) wasused because a disintegration test method according to the JapanesePharmacopoeia is different from the actual condition in the buccalcavity. In the DW method, while resulting tablets were placed on a No.20 wire cloth, onto which water was dropped at a speed of 4 ml/min., andthe time till the tablets fall down through the wire cloth was measuredas the disintegration time.

TABLE 1 sample/ compression pressure 150 kg 300 kg 450 kg 600 kg 800 kgComparison 1 Hardness hard to be hard to be hard to be 1.9 kgf 2.3 kgftableted tableted tableted disintegration — — — 20 sec. 22 sec.Embodiment 1 Hardness 1.9 kgf 3.9 kgf 5.1 kgf 6.2 kgf 7.3 kgfdisintegration 10 sec. l5 sec. 16 sec. 19 sec. 27 sec. Comparison 2Hardness hard to be hard to be hard to be 1.5 kgf 2.1 kgf tabletedtableted tableted disintegration — — — 18 sec. 21 sec. Embodiment 2Hardness 1.6 kgf 4.0 kgf 4.9 kgf 5.8 kgf 6.5 kgf disintegration 10 sec.16 sec. 20 sec. 25 sec. 29 sec.

In the Comparisons 1 and 2, it was found that it was hard to mold atablet by adding under 450 kg compression pressure but it was possibleto mold a tablet by adding more than around 600 kg compression pressure,while the hardness of the resulting tablets wasn't enough to practicaluse.

In the Embodiments 1 and 2, it was found that the tablet hardness enoughfor practical use could be obtained by adding more than 300 kgcompression pressure and its disintegration time was very fast.

When the resulting tablet produced at 450 kg compression pressureaccording to the Embodiment 1 was dosed, the tablet was disintegrated at10 seconds in the buccal cavity.

On the other hand, such resulting tablets with less than 30 seconds ofthe disintegration time of which testing was conducted in the abovementioned DW method were dissolved within 10 seconds in the buccalcavity, and represented such rapid disintegration speed that hasn't beenexperienced as a prior disintegrating tablets.

The tablets obtained by the Embodiments 3 were also measured of itshardness and disintegration time in the same way as above mentioned. Asthe result, the resulting tablets had enough hardness of about 6.5 kgfand its disintegration time was 10 seconds.

Embodiment 4

D-mannitol with average particle diameter of 60 μm (Towa Kasei Co.,Ltd.) was previously ground by a jet mill (Japan Pneumatic Co, Ltd.:type PJM-I-1.5) to obtain D-mannitol with average particle diameter of15 μm as first particle.

D-mannitol thus pulverized of 1880 g by weight and crosspovidone(POLYPLASDONE XL-10: ISP Co., Ltd.) of 100 g by weight were fed into amixing granulator (Powrex Corporation: type VG-25), mixed with eachother, and then the mixture was subjected to granulation with purifiedwater for growing. Thereafter, the granulated material thus grown wasdried by a fluid bed dryer to obtain a granulated material with averageparticle diameter of about 342 μm as second particle. Then 20 g ofmagnesium stearate was added into the granulated material and 200 g ofthe mixed granulated material were compressed and tabletted with arotary tabletting machine (CLEAN PRESS COLLECT TYPE 12, 8 mmφ flat mold,Kikusui Co., Ltd.) at a pressure of 500 kg.

Embodiment 5

Second particle with average particle diameter of 334 μm as a granulatedmaterial was produced from the first particle with average particlediameter of about 30 μm and a tablet was obtained by executingcompressing and tabletting as in the same manner as in the Embodiment 4.

[Comparison 3]

Second particle with average particle diameter of 315 μm as a granulatedmaterial was produced from the first particle with average particlediameter of about 60 μm and a tablet was obtained by executingcompressing and tabletting as in the same manner as in the Embodiment 4.

Embodiment 6

Second particle with average particle diameter of 158 μM as a granulatedmaterial was produced from the first particle with average particlediameter of about 15 μm and a tablet was obtained by executingcompressing and tabletting as in the same manner as in the Embodiment 4.

Embodiment 7

Second particle with average particle diameter of 554 μm as a granulatedmaterial was produced from the first particle with average particlediameter of about 15 μm and a tablet was obtained by executingcompressing and tabletting as in the same manner as in the Embodiment 4.

[Comparison 4]

D-mannitol with average particle diameter of 60 μm (Towa Kasei Co.,Ltd.) was previously ground by a jet mill (Japan Pneumatic Co., Ltd.:type PJM-I-1.5) to obtain D-mannitol with average particle diameter of15 μm as first particle.

D-mannitol thus pulverized of 1880 g by weight and crosspovidone(POLYPLASDONE XL-10: ISP Co., Ltd.) of 100 g by weight were fed into amixing granulator (Powrex Corporation: type VG-25), and mixed with eachother, then the mixture was subjected to granulation with purified waterwith 40 g of polyvinyl-pyrrolidone K30 dissolved for growing to obtain agranulated material. Then the granulated material thus grown was driedby a fluid bed dryer, thereby producing a granulated material withaverage particle diameter of about 350 μm as second particle.Thereafter, 20 g of magnesium stearate was added into the granulatedmaterial and 200 mg of the mixed granulated material was compressed andtabletted with a rotary tabletting machine (CLEAN PRESS COLLECT TYPE 12,8 mmφ flat mold, Kikusui Co., Ltd.) under a pressure of 500 kg toproduce a resulting tablet with a specific shape.

[Comparison 5]

Second particle with average particle diameter of 325 μm as a granulatedmaterial was produced from the first particle with average particlediameter of about 60 μm and a tablet was produced by executingcompressing and tabletting as in the same manner as in Comparison 4.

[Comparison 6]

1780 g of D-mannitol with average particle diameter of 60 μm was fedinto a mixing granulator (Powrex Corporation: type VG-25), was subjectedto granulation with purified water being dissolved with 200 g of maltosefor growing, and then dried to obtain a granulated material with averageparticle diameter of about 333 μm as second particle. Thereafter, 20 gof magnesium stearate was added into the granulated material and 200 mgof the mixed granulated material was compressed and tabletted with arotary tabletting machine (CLEAN PRESS COLLECT TYPE 12, 8 mmφ flat mold,Kikusui Co., Ltd.) under a pressure of 500 kg to produce a resultingtablet with a specific shape.

[Comparison 7]

D-mannitol with average particle diameter of 60 μm and crosspovidone(POLYPLASDONE XL-10: ISP Co., Ltd.) of 100 g by weight were fed into amixing granulator (Powrex Corporation: type VG-25), mixed with eachother, and then the mixture was subjected to granulation with purifiedwater with 200 g of maltose dissolved for growing, and then dried toobtain a granulated material with average particle diameter of about 339μm as second particle. Thereafter, 20 g of magnesium stearate was addedinto the granulated material and 200 g of the mixed granulated materialwas compressed and tabletted with a rotary tabletting machine (CLEANPRESS COLLECT TYPE 12, 8 mmφ flat mold, Kikusui Co., Ltd.) with apressure of 500 kg.

[Comparison 8]

D-mannitol with average particle diameter of 60 μm (Towa Kasei Co.,Ltd.) was previously ground by a jet mill (Japan Pneumatic Co., Ltd.:type PJM-I-1.5) to obtain D-mannitol with average particle diameter of15 μm as first particle. D-mannitol of 1840 g thus pulverized,crosspovidone (POLYPLASDONE XL-10: GAF Co., Ltd.) of 100 g were fed intoa mixing granulator (Powrex Corporation: type VG-25) to be mixed witheach other, and the mixture was subjected to granulation with purifiedwater dissolving 40 g of hydroxypropylcellulose (L-HPC, Shin-EtsuChemical Co., Ltd.) for growing. Then 20 g of magnesium stearate wasadded into the granulated material and 200 mg of the mixed material wascompressed and tabletted with a rotary tabletting machine (CLEAN PRESSCOLLECT TYPE 12, 8 mmφ flat mold, Kikusui Co., Ltd.) with a pressure of500 kg to obtain a resulting tablet with a specific shape.

The intrabuccal method in the table 2 was measured as follows:

Each one of five healthy adults took one tablet in the mouth and thetime the tablet was dissolved in the buccal cavity with saliva wasmeasured. The average value of five persons was calculated andconsidered as disintegration time in the buccal cavity.

TABLE 2 Effect of Particle Size on the hardness of resulting tablet 1st2nd hardness disintegration time (sec) particle particle (kg)intrabuccal DW JP Embodiment 4 15 342 5.2 kg 9 9 4 Embodiment 5 30 3343.5 8 10 5 Comparison 3 60 315 1.2 10 15 7 Embodiment 6 15 158 5.5 8 8 5Embodiment 7 15 554 5.6 10 7 5 Comparison 4 15 350 4.9 350 152 139Comparison 5 60 325 3.5 303 146 121 Comparison 6 60 333 3.5 286 125 105Comparison 7 60 339 4.1 215 99 95 Comparison 8 15 350 4.3 101 76 64

Preparation using a saccharide or a sugar alcohol which is firstparticle having an average particle diameter not more than 30 μm couldobtain a practical tablet hardness and rapid disintegration time despiteof the size of second particle. On the other hand, if a saccharide or asugar alcohol of which average particle diameter had 60 μm was used,rapid disintegration time was achieved but enough tablet hardness wasn'tobtained. Accordingly it was found that the size of first particle, notsecondary particle, was important in order to obtain enough tablethardness and rapid disintegration.

Comparing with disintegration time in a buccal cavity, that by DW methodand that by the Japanese Pharmacopeia (JP) method, the tablet showingabout 10 seconds of disintegration time in a buccal cavity showed thesame disintegration time in DW method and the JP method. However, thetablet showing more than 100 seconds of disintegration time in thebuccal cavity showed faster disintegration time in DW method and the JPmethod than that in the buccal cavity. Comparing DW method and the JPmethod, DW method showed disintegration time closer to that in thebuccal cavity. The tablet showing about 60 seconds of disintegrationtime in the JP method required about 100 seconds to be disintegrated inthe buccal cavity, namely it couldn't be rapidly disintegrated in thebuccal cavity.

Embodiment 8

D-mannitol with average particle diameter of 60 μm (Towa Kasei Co.,Ltd.) was previously ground by a jet mill (Japan Pneumatic Co., Ltd.:type PJM-I-1.5) to obtain D-mannitol with average particle diameter of20 μm as first particle. D-mannitol thus pulverized of 1710 g,donperidone of 170 g, and cross carmellose sodium of 100 g (Ac-Di-Sol,Asahi Kasei Corporation) were fed into a mixing granulator (PowrexCorporation: type VG-25) to be mixed with each other, and the mixturewas subjected to granulation with purified water for growing. Thereafterthe granulated material thus grown was dried by a fluid bed dryer andclassified by a No. 20 wire mesh. Then 20 g of magnesium stearate wasadded into the granulated material and 120 mg of thus obtained materialwas compressed and tabletted with a rotary tabletting machine (CLEANPRESS COLLECT TYPE 12, 8 mmφ flat mold, Kikusui Co., Ltd.) with apressure of 500 kg to obtain a resulting tablet of which hardness was4.2 kg, disintegration time in the buccal cavity was 28 seconds anddisintegration time by DW method was 26 seconds.

Embodiment 9

D-mannitol with average particle diameter of 60 μm (Towa Kasei Co.,Ltd.) was previously ground by a jet mill (Japan Pneumatic Co., Ltd.:type PJM-I-1.5) to obtain D-mannitol with average particle diameter of15 μm as first particle. D-mannitol of 1710 g thus pulverized,donperidone of 170 g, and low substituted hydroxypropylcellulose of 100g (L-HPC, Shin-Etsu Chemical Co., Ltd.) were fed into a mixinggranulator (Powrex Corporation: type VG-25) to be mixed with each other,and the mixtures was subjected to granulation with purified water forgrowing. Thereafter, the granulated material was dried by a fluid beddryer and classified by a No. 20 wire mesh. Then 20 g of magnesiumstearate was added into the granulated material and 120 mg of thusobtained material was compressed and tabletted with a rotary tablettingmachine (CLEAN PRESS COLLECT TYPE 12, 8 mmφ flat mold, Kikusui Co.,Ltd.) with a pressure of 500 kg to obtain a resulting tablet of whichhardness was 5.0 kg, disintegration time in the buccal cavity was 30seconds and disintegration time by DW method was 21 seconds.

Embodiment 10

D-mannitol (average particle diameter: 65 μm, Towa Kasei Co., Ltd.) waspreviously ground by a jet mill (Japan Pneumatic Co., Ltd.: typePJM-I-1.5) to obtain D-mannitol with average particle diameter of 25 μm.D-mannitol thus pulverized of 1790 g and donperidone of 100 g were fedinto a mixing granulator (Powrex Corporation: type VG-25) to be mixedwith each other, and the mixture was subjected to granulation withpurified water for growing. Thereafter, the granulated material thusgrown was dried by a fluid bed dryer (Gratt Co., Ltd.: WSG-type 5) andclassified by a No. 20 wire mesh. Then 1512 g of thus obtainedgranulated material, 80 g of crosspovidone (POLYPLASDONE XL-10: GAF Co.,Ltd.) and 8 g of magnesium stearate were mixed and compressed to betabeletted with a rotary tabletting machine (CLEAN PRESS COLLECT TYPE12, Kikusui Co., Ltd.). The tabletting conditions were such that theweight of tablet was 200 mg, the mold was 8 mm diameter and flat typeand the tabletting pressure was 800 kg. The obtained tablet had 5.7 kgfof hardness and 12 seconds of disintegration time by a DW method. Theactual disintegration time in the buccal cavity was about 10 seconds.

Embodiment 11

1790 g of pulverized D-mannitol which had been obtained like in theEmbodiment 10 was fed into a mixing granulator (Powrex Corporation: typeVG-25), and mixed with each other, then the mixture was subjected togranulation with purified water for growing. Thereafter, the granulatedmaterial thus grown was dried by a fluid bed dryer (Gratt Co., Ltd.:WSG-type 5) and classified by a No. 20 wire mesh. Then 1432 g of thusobtained granulated material, 80 g of donperidone as active ingredient,80 g of crosspovidone, 8 g of magnesium stearate were mixed andcompressed to be tabletted with a rotary tabletting machine (CLEAN PRESSCOLLECT TYPE 12, Kikusui Co., Ltd.). The tabletting conditions were thesame as the Embodiment 10. The obtained tablet had 5.2 kgf of hardnessand 14 seconds of disintegration time by a DW method. The actualdisintegration time in the buccal cavity was about 10 seconds.

Embodiment 12

1790 g of pulverized D-mannitol which had been obtained like in theEmbodiment 10 and 100 g of crosspovidone were fed into a mixinggranulator (Powrex Corporation: type VG-25), and mixed with each other,then the mixtures was subjected to granulation with purified water forgrowing. Thereafter, the granulated material thus grown was dried by afluid bed dryer (Gratt Co., Ltd.: WSG-type 5) and classified by a No. 20wire mesh. Then 1512 g of thus obtained granulated material, 80 g ofdonperidone as active ingredient, 8 g of magnesium stearate were mixedand compressed to be tabletted with a rotary tabletting machine (CLEANPRESS COLLECT TYPE 12, Kikusui Co., Ltd.). The tabletting conditionswere the same as the Embodiment 10. The obtained tablet had 5.9 kgf ofhardness and 12 seconds of disintegration time by DW method. The actualdisintegration time in the buccal cavity was about 10 seconds.

Embodiment 13

1790 g of pulverized D-mannitol which had been obtained like in theEmbodiment 10, 100 g of donperidone as active ingredient and 100 g ofcrosspovidone were fed into a mixing granulator (Powrex Corporation:type VG-25), and mixed with each other, then the mixture was subjectedto granulation with purified water for growing. Thereafter thegranulated material thus grown was dried by a fluid bed dryer (GrattCo., Ltd.: WSG-type 5) and classified by a No. 20 wire mesh. Then 1592 gof thus obtained granulated material, 8 g of magnesium stearate weremixed and compressed to be tabletted with a rotary tabletting machine(CLEAN PRESS COLLECT TYPE 12, Kikusui Co., Ltd.). The tablettingconditions were the same as the Embodiment 10. The obtained tablet had6.0 kgf of hardness and 15 seconds of disintegration time by DW method.The actual disintegration time in the buccal cavity was about 10seconds.

Embodiment 14

1790 g of pulverized D-mannitol which had been obtained like in theEmbodiment 10, 100 g of donperidone as active ingredient and 100 g ofcross carmellose sodium (Ac-Di-Sol, Asahi Kasei Corporation) were fedinto a mixing granulator (Powrex Corporation: type VG-25), and mixedwith each other, then the mixture was subjected to granulation withpurified water for growing. Thereafter the granulated material thusgrown was dried by a fluid bed dryer (Gratt Co., Ltd.: WSG-type 5) andclassified by a No. 20 wire mesh. Then 1592 g of thus obtainedgranulated material, 8 g of magnesium stearate were mixed and compressedto be tabletted with a rotary tabletting machine (CLEAN PRESS COLLECTTYPE 12, Kikusui Co., Ltd.). The tabletting conditions were the same asthe Embodiment 10. The obtained tablet had 4.5 kgf of hardness and 26seconds of disintegration time by DW method. The actual disintegrationtime in the buccal cavity was about 20 seconds.

Embodiment 15

1790 g of pulverized D-mannitol which had been obtained like in theEmbodiment 10, 100 g of donperidone as active ingredient and 100 g oflow substituted hydroxypropylcellulose (L-HPC, Shin-Etsu Chemical Co.,Ltd) were fed into a mixing granulator (Powrex Corporation: type VG-25),and mixed with each other, then the mixture was subjected to granulationwith purified water for growing. Thereafter, the granulated materialthus grown was dried by a fluid bed dryer (Gratt Co., Ltd.: WSG-type 5)and classified by a No. 20 wire mesh. Then 1592 g of thus obtainedgranulated material, 8 g of magnesium stearate were mixed and compressedto be tabletted with a rotary tabletting machine (CLEAN PRESS COLLECTTYPE 12, Kikusui Co., Ltd.). The tabletting conditions were the same asthe Embodiment 10.

The obtained tablet had 6.2 kgf of hardness and 25 seconds ofdisintegration time by W method. The actual disintegration time in thebuccal cavity was about 20 seconds.

Embodiment 16

1790 g of pulverized D-mannitol which had been obtained like in theEmbodiment 10, 100 g of donperidone as active ingredient and 100 g ofcrosspovidone were fed into a mixing granulator (Powrex Corporation:type VG-25), and mixed with each other, then the mixture was subjectedto granulation with purified water for growing. Thereafter, thegranulated material thus grown was dried by a fluid bed dryer (Gratt Co.Ltd.: WSG-type 5) and classified by a No. 20 wire mesh. Thus obtainedgranulated material was tabletted with a rotary tabletting machine (HataSeisakusho, Type AP-15) with a pressure of 500 kg while sprayingstearate magnesium from a lubricant spray attached to the tablettingmachine. The obtained tablet had 6.7 kgf of hardness and 12 seconds ofdisintegration time by a DW method. The actual disintegration time inthe buccal cavity was about 6 seconds.

According to the above-mentioned experimental data, it has beenconfirmed that the intrabuccally rapidly disintegrating tablet asmentioned in the present invention has enough practical hardness and canbe rapidly dissolved in the buccal cavity.

INDUSTRIAL APPLICABILITY

According to the present invention, a tablet which can be rapidlydisintegrated in oral cavity can be obtained.

1. A method of producing an intrabuccally rapidly disintegrating tablet,said intrabuccally rapidly disintegrating tablet comprising: a sugaralcohol or saccharide in the form of primary particles having an averageparticle size of not more than 30 μm; an active ingredient; and one ormore disintegrants selected from the group consisting of crospovidone,croscarmellose sodium, low substituted hydroxypropylcellulose, and amixture thereof, and said method comprising the steps of: (a)granulating a powder material comprising the sugar alcohol or saccharideand said active ingredient, thereby producing granulated material havinga predetermined size; (b) mixing said granulated material and said oneor more disintegrants; and (c) compressing the mixture into anintrabuccally rapidly disintegrating tablet.
 2. The method of claim 1,wherein the tablet disintegrates within 30 seconds, determined bymeasuring the time required for the tablet to fall through no. 10 wiremesh when water is added dropwise to the tablet at a rate of 4 mL/min.3. The method of claim 1, wherein the amount of active ingredient rangesfrom 0.01-30% by weight of the intrabuccally rapidly dispersing tablet.4. The method of claim 1, wherein the sugar alcohol or saccharide ispulverized in advance to an average particle size of not more than 30μm.
 5. The method of claim 1, wherein the sugar alcohol or saccharide isselected from the group consisting of mannitol, lactose, and mixturesthereof.
 6. The method of claim 1, wherein said method further comprisesmixing the granulated material with a lubricant before said compressingstep.
 7. The method of claim 1, further comprising spraying a lubricanton material contacting surfaces of punches and dies of a tablettingmachine before said compressing step.
 8. The method of claim 6, whereinsaid granulating step comprises granulating a sugar alcohol orsaccharide, said active ingredient, and said one or more disintegrantsto produce a granulated material.
 9. The method of claim 7, wherein saidgranulating step comprises granulating a sugar alcohol or saccharide,said active ingredient, and said one or more disintegrants to produce agranulated material.
 10. The method of claim 6, wherein saidintrabuccally rapidly disintegrating tablet comprises about 60-95% byweight of said sugar alcohol or saccharide and about 1-10% by weight ofsaid disintegrant.
 11. The method of claim 7, wherein said intrabuccallyrapidly disintegrating tablet comprises about 60-95% by weight of saidsugar alcohol or saccharide and about 1-10% by weight of saiddisintegrant.
 12. The method of claim 1, wherein said method comprises:(a-1) granulating a wet formulation comprising said sugar alcohol orsaccharide, said active ingredient, thereby producing granulatedmaterial having a predetermined size; (a-2) drying the granulatedmaterial; (b) mixing the dried granulated material and said one or moredisintegrants; and (c) compressing the mixture into an intrabuccallyrapidly disintegrating tablet.
 13. An intrabuccally rapidlydisintegrating tablet, made by the process of claim
 1. 14. Anintrabuccally rapidly disintegrating tablet, made by the process ofclaim
 6. 15. An intrabuccally rapidly disintegrating tablet, made by theprocess of claim
 7. 16. An intrabuccally rapidly disintegrating tablet,made by the process of claim 12.